http://intl.elsevierhealth.com/journals/mehy
a,b,*
, Lanier W. Rossignol
Blue Ridge Medical Center, 4038 Thomas Nelson Highway, Arrington, VA 22922, USA University of Virginia, P.O. Box 800729, Charlottesville, VA, USA
Summary Autism is a neurodevelopmental disorder that currently affects as many as 1 out of 166 children in the United States. Recent research has discovered that some autistic individuals have decreased cerebral perfusion, evidence of neuroinammation, and increased markers of oxidative stress. Multiple independent single photon emission computed tomography (SPECT) and positron emission tomography (PET) research studies have revealed hypoperfusion to several areas of the autistic brain, most notably the temporal regions and areas specically related to language comprehension and auditory processing. Several studies show that diminished blood ow to these areas correlates with many of the clinical features associated with autism including repetitive, self-stimulatory and stereotypical behaviors, and impairments in communication, sensory perception, and social interaction. Hyperbaric oxygen therapy (HBOT) has been used with clinical success in several cerebral hypoperfusion syndromes including cerebral palsy, fetal alcohol syndrome, closed head injury, and stroke. HBOT can compensate for decreased blood ow by increasing the oxygen content of plasma and body tissues and can even normalize oxygen levels in ischemic tissue. In addition, animal studies have shown that HBOT has potent anti-inammatory effects and reduces oxidative stress. Furthermore, recent evidence demonstrates that HBOT mobilizes stem cells from human bone marrow, which may aid recovery in neurodegenerative diseases. Based upon these ndings, it is hypothesized that HBOT will improve symptoms in autistic individuals. A retrospective case series is presented that supports this hypothesis. c 2006 Elsevier Ltd. All rights reserved.
Background
Overview of autism
Abbreviations: SPECT, single photon emission computed tomography; PET, positron emission tomography; HBOT, hyperbaric oxygen therapy; MRI, magnetic resonance imaging; ATA, atmosphere absolute; CP, cerebral palsy; SOD, superoxide dismutase. * Corresponding author. Tel.: +1 434 263 4000; fax: +1 434 263 4160. E-mail addresses: dlross7@hotmail.com (D.A. Rossignol), dlross7@hotmail.com (L.W. Rossignol).
Autism is a neurodevelopmental disorder currently affecting as many as 1 out of 166 children in the United States [1] that is characterized by impairments in social interaction, difculty with communication, and restrictive and repetitive behaviors [2]. It affects children from all socioeconomic and ethnic backgrounds [3]. Autism was considered
0306-9877/$ - see front matter c 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2006.02.009
Hyperbaric oxygen therapy may improve symptoms in autistic children a rare condition before the 1990s with a prevalence of approximately 1 in 2500 children [4]. However, according to the US Department of Developmental Services, the prevalence of autism spectrum disorders increased 556% from 1991 to 1997 [5]. Autism is now more common than childhood cancer, cerebral palsy, Downs syndrome, spina bida, or cystic brosis [6,7]. In addition, autism is found throughout the globe and the prevalence worldwide is increasing 3.8% per year [8]. Autism is an incompletely understood disorder [3,5], but new clinical research is beginning to unravel some of its mysteries.
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approximately 2% of patients. The incidence of such barotrauma is decreased with pseudoephedrine treatment before HBOT. Less common side effects in descending order include sinus squeeze, serous otitis, claustrophobia, and reversible myopia. Seizures may occur infrequently in about 0.010.03% of patients [9].
Hypothesis
Multiple studies have revealed that autism is a neurodegenerative disease characterized by cerebral hypoperfusion, neuroinammation, and increased oxidative stress. HBOT helps overcome hypoperfusion, has potent anti-inammatory effects and reduces oxidative stress. Furthermore, HBOT mobilizes stems cells from human bone marrow. Therefore, HBOT will improve symptoms of autism.
218 blood ow and concomitantly increased middle cerebral arterial resistance upon auditory stimulation. Conversely, control neurotypical and mentally retarded children showed opposite results [45]. The mechanism of this abnormal change in cerebral arterial resistance in autistic children is unknown. However, several studies have shown that astrocytes can regulate cerebral blood ow. Astrocytes can directly cause arteriole vasoconstriction through a calcium mechanism [46] and arteriole vasodilatation through a cyclooxygenase medium [47]. Neurons, astrocytes, and vascular cells compose a functional unit that maintains proper blood ow and oxygenation for the brain [48]. Neural activity normally causes increased cerebral blood ow thus delivering increased oxygen [44]. However, a recent study found evidence of neuroinammation and astroglial activation in autism [49]. It is possible that astroglial inammation may affect the control of blood ow regulated by astrocytes and lead to the abnormal changes in cerebral artery resistance and hypoperfusion seen in some autistic children. Furthermore, inammation is a known cause of decreased blood ow and several inammatory conditions have associated cerebral hypoperfusion including lupus [50,51], Sjo grens syndrome [52], Behc ets disease [53], viral encephalitis [54,55], and acute Kawasaki disease [40]. One SPECT study of 27 children with echovirus meningitis demonstrated decreased cerebral blood ow in 74% of the children [55] and two recent SPECT studies revealed impaired cerebral perfusion in 81% of patients with Sjo grens syndrome [52]. In one SPECT study of patients with systemic lupus erythematosus, 59% had evidence of cerebral hypoperfusion [51]. Furthermore, treatment of the inammation found in lupus with iloprost [56] and methylprednisolone [57] normalized cerebral blood ow on follow-up SPECT scans. It is conceivable that the cerebral hypoperfusion found in autistic children may be triggered by neuroinammation and therefore may be reversible with anti-inammatory modalities.
Rossignol and Rossignol iors including resistance to changes in routine and environment [29]. Hypoperfusion of the temporal lobes has also been linked with increased autism symptom prole scores including obsessive desire for sameness and impairments in communication and social interaction [31]. Another study on high functioning autistics demonstrated decreased blood ow to areas of the temporal lobe and amygdala, which was correlated with clinical impairments in processing facial expressions and emotions [42]. This was conrmed by a recent study of autistics demonstrating diminished blood ow to the fusiform face area responsible for recognizing familiar faces [58]. In addition, decreased perfusion of the temporal lobes is a consistent nding in many studies of autistic children. Two larger controlled studies (2123 autistic children) using SPECT and PET scans conrmed signicant bitemporal hypoperfusion [31,34]. In both of these studies, the control group was mentally retarded; therefore, the hypoperfusion could not be attributed to mental retardation alone [33,34]. Another SPECT study of 31 autistic children, 16 of whom had epilepsy, also demonstrated reduction of cerebral blood ow to the temporal lobes. Of note, cerebral blood ow was not different between those with and without epilepsy, suggesting that epilepsy itself was not associated with hypoperfusion in these individuals [37]. A more recent PET study of 11 autistic children revealed diminished blood ow to the left temporal area, including Wernickes area (which is involved in language comprehension) and Brodmanns area 21 (involved in auditory processing and language), when compared to age-matched mentally retarded children [39]. Interestingly, an association between temporal lobe abnormalities [59] and the subsequent development of secondary autism has been described in tuberous sclerosis [60], infantile spasms [61], herpes simplex encephalitis [62,63], and an acute encephalopathic illness in children [64]. The relative amount of cerebral hypoperfusion in autistic children can vary by age. In one study, hypoperfusion of the prefrontal and left temporal areas worsened and became quite profound as the age of the autistic child increased. This diminished perfusion correlated with decreased language development. The authors concluded that hypoperfusion subsequently prevents development of true verbal uency and development in the temporal and frontal areas associated with speech and communication [27]. Hypoperfusion of the temporal and other brain regions has been correlated with many of the clinical ndings associated with autism including self-
Zones of the autistic brain affected by decreased blood ow and symptom correlations
Cerebral hypoperfusion may play a role in some of the more unusual characteristics of autistic behavior. Diminished blood ow to the thalamus has been correlated with the autistic clinical features of repetitive, self-stimulatory, and unusual behav-
Hyperbaric oxygen therapy may improve symptoms in autistic children stimulatory behaviors and impairments in communication, sensory perception, and social interaction [33,34]. This diminished blood ow may be mediated by neuroinammation. Further studies on the effects of inammation on blood ow in the autistic brain are needed, especially studies involving the temporal lobes where hypoperfusion is common. Whatever the cause of the hypoperfusion, the possibility exists that the enhancement of oxygen delivery to the brain accomplished by HBOT may improve some of the symptoms found in autistic children.
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In addition, HBOT has been used in several studies on children with cerebral palsy (CP). Some children with CP due to perinatal asphyxia have focal areas of cerebral hypoperfusion on SPECT scans [75]. Signicant clinical improvements were found in one study of children with CP after 20 sessions of HBOT at 95% oxygen and 1.75 ATA [76]. Other studies using HBOT in cerebral hypoperfusion disorders have been performed at lower pressures (1.5 ATA or less). Stoller recently reported on one pediatric case of fetal alcohol syndrome, which is considered irreversible and incurable [13] and is characterized by cerebral hypoperfusion on SPECT studies [77]. Using HBOT at 1.5 ATA, the child had statistically signicant improvements in verbal, memory, reaction time, impulse control, and visual motor scores [13]. In addition, Heuser et al. [78] treated a four year old autistic child using lower pressure HBOT at 1.3 ATA and reported striking improvement in behavior including memory and cognitive functions after only ten sessions. Furthermore, the child had improvement of cerebral hypoperfusion as measured by pre-HBOT and post-HBOT SPECT scans [78]. These case reports are notable because they demonstrate that some irreversible and permanent neurological conditions can have clinical improvements with HBOT. The number of HBOT sessions needed to produce full clinical improvements from cerebral hypoperfusion or ischemia is unclear. In one study combining the use of SPECT and HBOT, an average of 70 treatments was needed to show a signicant increase in cerebral blood oxygenation and metabolism in patients with chronic neurological disorders including CP, stroke, and traumatic brain injury. Of note, the rate of improvement in cerebral blood oxygenation was more profound during the last 35 treatments compared to the rst 35 [79]. In addition, reports from some HBOT researchers indicate that younger patients tend to have improvements more quickly than older patients [79]. Therefore, older patients may need more treatments. Since many autistic children experience at least a mild degree of cerebral hypoperfusion, this decreased blood ow could lead to an element of brain hypoxia. Multiple SPECT studies have shown evidence of relative brain hypoxia in certain cerebral hypoperfusion syndromes, including autism [78], which improved after HBOT [14,65,78,79]. It is certainly plausible that the increased oxygen delivery by HBOT could overcome any hypoxia caused by hypoperfusion and thus lead to improvements in the symptoms of autistic children.
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Rossignol and Rossignol showed increased survival and decreased proteinuria, anti-dsDNA antibody titers, and immune-complex deposition in lupus-prone autoimmune mice [98]. Furthermore, HBOT has been used in animal studies to improve colitis [93]. Interestingly, thirty sessions of HBOT at 2.0 ATA has been used in humans to achieve remission of ulcerative colitis not responding to conventional therapies [99]. This may be relevant in autistic children given the higher prevalence of gastrointestinal mucosal inammation described previously. Given the results of these studies, it is certainly plausible that HBOT can decrease both neuroinammation and gastrointestinal inammation in autistic children and thereby potentially lead to improvements in symptoms.
Hyperbaric oxygen therapy may improve symptoms in autistic children 2.0 ATA reduced brain damage without increasing oxidative stress [105]. Furthermore, in a rat model of reperfusion, HBOT extended skin ap life without evidence of oxidative stress [106]. In addition, numerous studies have shown improvements in oxidative stress with HBOT including increased production of antioxidants and antioxidant enzymes and decreased markers of oxidative stress such as malondialdehyde [105,107,108]. An improvement in the survival rate of skin aps and an increase in SOD levels were found in one study when rats were exposed to hyperbaric oxygen at 2.0 ATA [109]. In another study, HBOT at 2.5 ATA induced the production of antioxidants and decreased malondialdehyde levels in rats [107]. Furthermore, in a study of rats with pancreatitis, HBOT at 2.5 ATA decreased oxidative stress markers including malondialdehyde, and increased the levels of the anti-oxidant enzymes glutathione peroxidase and SOD [108]. HBOT has also been shown to acutely raise the levels of reduced glutathione in the plasma and lymphocytes of some humans after just one treatment session at 2.5 ATA [110]. Finally, ischemia-reperfusion injuries usually cause oxidative stress through decreases in glutathione levels and activities of catalase and SOD. However, in one rat study of ischemia, pretreatment with 13 doses of HBOT caused an increase in liver glutathione and SOD levels and protected against liver injury; control animals not receiving HBOT actually had drops in glutathione and anti-oxidant enzyme levels and had concomitant liver damage [111].
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effects in the human body [117119]. The production of small amounts of oxygen radicals may confer protection from future hypoxia and this effect has been termed ischemic tolerance. In one animal study, pre-treatment with HBOT at 2.0 ATA prior to an ischemia insult induced ischemic tolerance whereas pre-treatment at 3.0 ATA did not, possibly because this higher pressure may have generated too many oxygen radicals [116]. Nevertheless, many studies demonstrate that HBOT lowers oxidative stress. Furthermore, oxidative stress appears to be less of a concern at pressures under 2.0 ATA, which are often used clinically [116]. In spite of this, therapies to raise glutathione levels [100] and the use of antioxidants [120] may be benecial in patients with conditions of increased oxidative stress before HBOT is contemplated. Several antioxidant supplements have been found to attenuate oxidative stress induced by high pressure HBOT including a-lipoic acid [112], melatonin [121], N-acetylcysteine [111,122], vitamin E [123], riboavin [124], selenium [123,124], and glutathione [125]. Based upon these ndings, a combination of antioxidants and HBOT may help reduce oxidative stress in autistic children and lead to improvements in symptoms.
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Table 1 Autism . Cerebral perfusion m Inammation m Oxidative stress Neurodegenerative disease Summary of HBOT use in autism HBOT m . . m Perfusion to brain tissue Inammation Oxidative stress Stem cells
Rossignol and Rossignol fusion disorders [1315,65], it was hypothesized that low pressure HBOT would also help autism, a disease in which cerebral hypoperfusion is an integral component [31,32]. Recently, evidence has accumulated that low pressure hyperbaric therapy at 1.3 ATA and less than 100% delivered oxygen may improve symptoms in some diseases associated with cerebral hypoperfusion. For instance, one study using hyperbaric therapy at 1.3 ATA and room air demonstrated clinical improvements in some children with CP [129,130], a disease shown to have evidence of diminished cerebral blood ow [75]. Furthermore, one case report indicated striking improvement in a 4 year old child with autism after using hyperbaric therapy for 10 sessions at 1.3 ATA and room air. The child also had improvement of cerebral hypoperfusion as measured by pre-HBOT and post-HBOT SPECT scans [78]. Based upon these ndings, it was hypothesized that low pressure HBOT would improve symptoms of autism. A retrospective case series was examined to evaluate this hypothesis. A review of the medical literature was performed using MEDLINE and Google Scholar and no clinical studies were found on the use of HBOT in autistic children.
and/or oxidative stress, including autism, through the improvement of oxygen supply, decreased inammation and oxidative stress, and/or the recruitment of new stem cells (see Table 1). This in turn should lead to improved clinical outcomes. Some physicians have begun using HBOT in autistic children and anecdotal reports indicate that HBOT has improved symptoms in autistic children including enhancements in socialization, language, and repetitive behaviors [78,128]. A recent retrospective case series also indicates that low pressure HBOT may improve symptoms in autistic children (see Appendix A). Further research in this area, including HBOT trials in autistic patients, is urgently needed to test this hypothesis.
Acknowledgments
The authors thank the following for reviewing this manuscript and offering advice: Dr. John Battiston, Dr. Bentley Calhoun, Mr. Michael Haynes, Dr. Elizabeth Mumper, Dr. David Slawson, and Dr. Kyle Van Dyke. Written consent was obtained from the childrens parent(s) for publication of case series data. The authors have two autistic sons who participated in the case series.
Methods
This study is a retrospective analysis of 6 autistic children who underwent low-pressure HBOT. All 6 children had a prior diagnosis of autism (DSM-IV 299.00) by an outside physician and none of the children had previously received HBOT. In the normal course of treatment, parent-rated scales were obtained pre-treatment and post-treatment. The University of Virginia Institutional Review Board for Health Sciences Research approved our retrospective examination of cases in this study and for the use of this data for publication. Informed consent was obtained from each childs parent(s) prior to starting HBOT. All 6 children started and 5 completed 40 1 h sessions of low pressure HBOT at 1.3 ATA and 2830% oxygen (after adjustment for the pressure effect) over a three month period. One child (Child C) only nished twenty-ve sessions due to scheduling conicts and was included in the analysis. All 6 children were taking multiple antioxidant supplements before starting HBOT. Children were allowed to continue all current therapies and to add new ones during HBOT. The characteristics of the children, including age and sex, are found in Table 2. A low pressure hyperbaric chamber was used. Room air mixed with oxygen from an oxygen concentrator was pumped into the pressurized
Appendix A. Low pressure hyperbaric oxygen therapy1 improves symptoms in autistic children: A retrospective case series
Background
Since low pressure HBOT (under 1.5 ATA) improved symptoms in some patients with cerebral hypoper1 Hyperbaric oxygen therapy (HBOT) normally refers to inhaling 100% oxygen at greater than 1 ATA in a pressurized chamber [9]. However, for the purposes of this case series, the treatment with hyperbaric pressure at 1.3 ATA augmented with 2830% oxygen is referred to as HBOT. Hyperbaric pressure at 1.3 ATA and room air is simply termed hyperbaric therapy.
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Patient characteristics and scoresa Age 2 4 3 7 6 7 Sex M M M M F F ATEC before HBOT 40 91 75 35 88 24 ATEC after HBOT 22 55 64 32 80 22 CARS before HBOT 21 37.5 45 27 41.5 23 CARS after HBOT 17 30 38 25 39.5 22 SRS before HBOT 98 154 135 94 139 54 SRS after HBOT 44 110 121 62 121 67
Declining scores indicate improvement on these scales. Received only 25 HBOT treatments.
Table 3 Age
Average score changesa by age ATEC before HBOT 68.7 49.0 58.8 ATEC after HBOT 47.0 44.7 45.8 CARS before HBOT 34.5 30.5 32.5 CARS after HBOT 28.3 28.8 28.6 SRS before HBOT 129.0 95.7 112.3 SRS after HBOT 91.7 83.3 87.5
chamber, resulting in a nal chamber oxygen concentration of 2830% by direct oximetry measurement using a Moxy oxygen monitor and after adjustment for the pressure effect. Multiple random oximetry measurements were taken on different treatment days to verify the consistency of the chamber oxygen concentration, which uniformly remained 2830%. Parent rated pre-treatment scores and post-treatment scores were calculated for each subject (see Table 2) using the Autism Treatment Evaluation Checklist (ATEC), Childhood Autism Rating Scale (CARS), and Social Responsiveness Scale (SRS). ATEC is a scoring system of verbal communication, sociability, sensory/cognitive awareness, and health/autistic behaviors published by the Autism Research Institute [131]. CARS is a widely used scale for screening and diagnosing autism and has been shown to correlate very well with
the DSM-IV criteria for autism diagnosis [132]. SRS is a recently validated test of interpersonal behavior, communication, and stereotypical traits in autism [133].
Results
Low pressure HBOT was well tolerated by all 6 children with no adverse effects noted. More dramatic improvements were found in children age 4 and under when compared to those in the older group (Table 3). ATEC score results The average improvement in all children on ATEC was 22.1% (p = 0.0538) ( Fig. 1). ATEC scores improved by 31.6% in the younger group compared to 8.8% in the older group (Fig. 2).
Child C Child D
Child E Child F
80 60
80
Score
Score
60 40 20 0
Before HBOT
After 40 HBOT
Before HBOT
After 40 HBOT
Figure 1
Figure 2
224 CARS score results The average improvement in all children on CARS was 12.1% (p = 0.0178) (Fig. 3). CARS improved
Rossignol and Rossignol 18.0% in the younger group and 5.6% in the older group (Fig. 4). SRS score results The average improvement in all children on SRS was 22.1% (p = 0.0518) (Fig. 5). SRS improved 28.9% in the younger group and 13.0% in the older group (Fig. 6).
Child C Child D
Child E Child F
Discussion
Autism is characterized, in part, by decreased cerebral blood ow [31,32]. Low pressure HBOT has been used in some cerebral hypoperfusion conditions including CP. Recently, a study demonstrated that some children with CP had clinical improvements using hyperbaric therapy at 1.3 ATA. In this study, 111 patients with CP and a history of hypoxia in the perinatal period had statistically signicant clinical improvements in gross motor function, memory, attention, and language production after hyperbaric therapy. One group received lower pressure hyperbaric therapy at 1.3 ATA and room air while the other group was given higher pressure HBOT at 1.75 ATA and 100% oxygen. Interestingly, the improvements in symptoms were statistically equivalent in the two groups [129]. Most of the improvements continued for 3 months after treatment and some of the children from the study began walking, speaking, and sitting for the rst times in their lives [130]. However, it must be noted that this study was controversial, as children in the lower pressure group improved equally with children in the higher pressure group. However, based on these ndings, it was hypothesized that low-pressure HBOT could potentially improve symptoms in autistic children. This case series suggests that low pressure HBOT may indeed be benecial in the treatment of autism. An interesting nding from this case series was that the younger children had more signicant improvements in clinical outcome scores than the older children. This is congruent with reports from some HBOT researchers indicating that younger patients tend to have improvements more quickly than older patients [79]. This effect may be partially explained by the ndings of a previous study, which showed that autistic children aged 34 years experience diminished frontal lobe blood ow compared to age-matched neurotypical children [41]. It is possible that HBOT in younger autistic children can improve cerebral oxygenation and thus overcome the effects of hypoperfusion and aid these children in catching up with their neurotypical
Before HBOT
After 40 HBOT
Figure 3
Before HBOT
After 40 HBOT
Figure 4
Child C Child D
Child E Child F
Score
Before HBOT
After 40 HBOT
Figure 5
Before HBOT
After 40 HBOT
Figure 6
Hyperbaric oxygen therapy may improve symptoms in autistic children peers. Furthermore, the younger children in this case series may have had less overall hypoperfusion to surmount because decreased cerebral blood ow to areas associated with communication has been shown to worsen with increasing age in autistic children [27]. It is likely that the older children in this case series need more than 40 HBOT sessions to show further improvements, especially since some HBOT researchers have noted that 5080 HBOT sessions are typically needed to show significant clinical gains [79]. In addition, the chamber was augmented with only 2830% oxygen instead of 100% oxygen. It is possible that the children in this case series may have experienced more improvements if 100% oxygen and/or a higher pressure had been used. These speculations certainly warrant further testing. This case series did have several inherent limitations. Children were allowed to continue all other therapies for autism and also add new ones, such as supplements. Therefore, other therapies could have contributed to the some of the clinical gains. Parents were not blinded to the fact that their children received HBOT and evaluation of the children was through parent-rated scales, either of which could lead to bias. There was no placebo or control group. Thus, the improvements could have been due merely to the natural development of the children, although none of the parents reported their child as undergoing developmental spurts of similar or greater magnitude in the recent past. Finally, this series lacked power because the sample size was small. Despite these limitations, the analysis of this case series suggests substantial clinical benets were produced, and therefore, this hypothesis needs to be tested in a formal prospective study.
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Conclusions
HBOT has been shown to increase oxygen delivery to hypoperfused or hypoxic tissues, decrease inammation and oxidative stress, and mobilize stem cells from human bone marrow. The mechanism of clinical improvements in ATEC, CARS, and SRS scores in the children studied may be secondary to increased oxygenation of underperfused areas of the autistic brain, reduced neuroinammation, decreased oxidative stress, or a combination of these. This case series suggests that low pressure HBOT improves symptoms in autistic children. Further research in this area, including HBOT trials in autistic patients, using observers blinded to the intervention, is now needed to test this hypothesis.
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